Rosuvastatin was first disclosed in EP 521471. This patent also disclosed a process for the preparation of rosuvastatin via methyl ester of rosuvastatin, methyl (E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate, (thereon MER) which is one of the key intermediate in the synthesis of rosuvastatin. Processes for the preparation of rosuvastatin via MER are also disclosed in WO 03/016317, WO 03/097614, WO 06/017357. MER is described as “syrup” in the above mentioned publications. On the other hand, WO 05/042522 discloses crystalline ethyl, iso-propyl, tert-butyl esters of rosuvastatin.
While MER is converted to rosuvastatin salt in one (or two) step reaction, the purity of rosuvastatin is greatly affected by the purity of MER. Therefore, there is a need for developing improved process for the preparation of pure MER.
A “chromatographically pure methyl ester of rosuvastatin” in the present invention means chromatographically purified substance, obtained from collected fraction of eluent, containing substantially only MER, in other words: chromatographically pure substance is obtained by chromatography under conditions that a single peak, corresponding to that substance will be eluted and will substantially not overlap with peaks for other substances. In particular this will mean MER having less than 0.5% of substances different from 3S,5R, or 3R,5S of methyl ester of rosuvastatin.
An “enantiomerically pure MER” means MER containing more than 99% of 3R,5S eneantiomer, that is consequently less than 1% of 3S,5R, preferably less than 0.5% of 3S,5R, more preferably less than 0.1% of 3S,5R enantiomer. The % above refer to area.
It was found that MER can be obtained in crystalline form. It was especially surprising, that only a mixture of MER enantiomers is able to crystallize. Consequently, if a solution contains an excess of desired enantiomer, the mixture of enantiomers will crystallize, leaving only desired enantiomer in solution.